Variant 17-63601263-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016360.4(TACO1):c.180C>A(p.His60Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TACO1
NM_016360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.11

Variant links:

Genes affected

TACO1 (HGNC:24316): (translational activator of cytochrome c oxidase I) This gene encodes a mitochondrial protein that function as a translational activator of mitochondrially-encoded cytochrome c oxidase 1. Mutations in this gene are associated with Leigh syndrome.[provided by RefSeq, Mar 2010]

TACO1 links:

ENSG00000288894 (HGNC:):

ENSG00000288894 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TACO1	NM_016360.4 linkuse as main transcript	c.180C>A	p.His60Gln	missense_variant	1/5	ENST00000258975.7	NP_057444.2	Q9BSH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TACO1	ENST00000258975.7 linkuse as main transcript	c.180C>A	p.His60Gln	missense_variant	1/5	1	NM_016360.4	ENSP00000258975.6	Q9BSH4
ENSG00000288894	ENST00000690765.1 linkuse as main transcript	n.*107-3271C>A		intron_variant				ENSP00000510085.1
TACO1	ENST00000684587.1 linkuse as main transcript	c.180C>A	p.His60Gln	missense_variant	1/5			ENSP00000507435.1	A0A804HJB7
TACO1	ENST00000581120.1 linkuse as main transcript	n.382C>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000287

AC:

AN:

243968

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459486

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 60 of the TACO1 protein (p.His60Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TACO1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2067109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TACO1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.79

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.80

Loss of catalytic residue at N61 (P = 0.0648);

MVP

0.34

MPC

1.3

ClinPred

0.96

GERP RS

2.3

Varity_R

0.99

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over